Methods of treating cerebral edema and spinal cord edema
View Patent ↗The present invention relates to the use of selective aquaporin inhibitors, e.g., of aquaporin-4 or aquaporin-2, e.g., certain phenylbenzamide compounds, for the prophylaxis, treatment and control of aquaporin-mediated conditions, e.g., diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord, e.g., following trauma or ischemic stroke, as well as the edema associated with glioma, meningitis, acute mountain sickness, epileptic seizures, infections, metabolic disorders, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, and lupus cerebritis, as well as edema consequent to microgravity and/or radiation exposure, as well as edema consequent to invasive central nervous system procedures, e.g., neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, or deep brain stimulation, as well as retinal edema), as well as hyponatremia and excess fluid retention, and diseases such as epilepsy, retinal ischemia and other diseases of the eye associated with abnormalities in intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines, as well as to novel assays for identifying aquaporin inhibitors.
1. A method of treating or controlling a disease or condition mediated by an aquaporin selected from cytotoxic cerebral edema and spinal cord edema comprising administering to a human patient in need thereof an effective amount of an aquaporin inhibitor of formula 1a:
wherein:
R 1 , R 2 , R 3 , R 4 , and R 5 are selected from H, halo, halogenated C 1-4 alkyl, and cyano; and
R 6 is selected from H and physiologically hydrolysable and acceptable acyl;
in free or pharmaceutically acceptable salt form.
2. The method of claim 1 , wherein:
R 1 is selected from trifluoromethyl, chloro, fluoro, and bromo;
R 3 and R 5 are the same or different and selected from trifluoromethyl, chloro, fluoro, and bromo; and
R 2 and R 4 are both H.
3. The method of claim 2 , wherein:
R 1 is selected from chloro and bromo;
R 3 and R 5 are both trifluoromethyl; and
R 2 , R 4 and R 6 are all H.
4. The method of claim 1 , wherein R 6 is a phosphono group, which may be substituted or unsubstituted.
5. The method of claim 1 , wherein the aquaporin inhibitor of formula 1a is selected from
6. The method of claim 1 , wherein the aquaporin inhibitor of formula 1a is
in free form.
7. The method of claim 1 , wherein the aquaporin inhibitor of formula 1a is
in free or pharmaceutically acceptable salt form.
8. The method of claim 6 , wherein the condition to be treated or controlled is cytotoxic cerebral edema.
9. The method of claim 8 , wherein the cytotoxic cerebral edema is consequent to a head trauma, a stroke, a glioma, meningitis, acute mountain sickness, an epileptic seizure, an infection, a metabolic disorder, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, or diabetic ketoacidosis.
10. The method of claim 8 , wherein the cytotoxic cerebral edema is consequent to an abscess, eclampsia, Creutzfeldt-Jakob disease, or lupus cerebritis.
11. The method of claim 8 , wherein the cytotoxic cerebral edema is consequent to microgravity exposure, radiation exposure, or an invasive central nervous system procedure.
12. The method of claim 9 , wherein the cytotoxic cerebral edema is consequent to a head trauma, a stroke, a glioma, meningitis, acute mountain sickness, an epileptic seizure, hypoxia, hepatic failure, hepatic encephalopathy, or diabetic ketoacidosis.
13. The method of claim 9 , wherein the cytotoxic cerebral edema is consequent to a stroke.
14. The method of claim 13 , wherein the cytotoxic cerebral edema is consequent to an ischemic stroke.
15. The method of claim 9 , wherein the cytotoxic cerebral edema is consequent to a head trauma.
16. The method of claim 8 , wherein the cytotoxic cerebral edema is consequent to a traumatic brain injury.
17. The method of claim 6 , wherein the condition to be treated or controlled is spinal cord edema.
18. The method of claim 17 , wherein the spinal cord edema is consequent to spinal cord trauma.
19. The method of claim 18 , wherein the spinal cord trauma is spinal cord compression.
20. The method of claim 8 , wherein the patient has suffered a stroke or head injury within 12 hours of commencing treatment.
21. The method of claim 8 , wherein the patient has suffered a stroke or head injury within 6 hours of commencing treatment.
22. The method of claim 8 , wherein the patient has suffered a stroke or head injury within 3 hours of commencing treatment.
23. The method of claim 6 , wherein the condition to be treated or controlled is cytotoxic cerebral edema consequent to hypoxia.
24. The method of claim 23 , wherein the hypoxia is caused by cardiac arrest or other interruption of blood perfusion to the brain.
25. The method of claim 23 , wherein the hypoxia is caused by a stroke.
26. The method of claim 1 , wherein the aquaporin inhibitor of formula 1a is
in free or pharmaceutically acceptable salt form.
27. The method of claim 26 , wherein the condition to be treated or controlled is cytotoxic cerebral edema.
28. The method of claim 27 , wherein the cytotoxic cerebral edema is consequent to a head trauma, a stroke, or hypoxia.
29. The method of claim 28 , wherein the cytotoxic cerebral edema is consequent to an ischemic stroke.
30. The method of claim 27 , wherein the cytotoxic cerebral edema is consequent to a traumatic brain injury.
31. The method of claim 28 , wherein the hypoxia is caused by cardiac arrest, a stroke, or other interruption of blood perfusion to the brain.
32. The method of claim 17 , wherein the patient has suffered a spinal injury within 12 hours of commencing treatment.
33. The method of claim 17 , wherein the patient has suffered a spinal injury within 6 hours of commencing treatment.
34. The method of claim 17 , wherein the patient has suffered a spinal injury within 3 hours of commencing treatment.
35. The method of claim 7 , wherein the condition to be treated or controlled is spinal cord edema.
36. The method of claim 35 , wherein the spinal cord edema is consequent to spinal cord trauma.
37. The method of claim 36 , wherein the spinal cord trauma is spinal cord compression.
38. The method of claim 35 , wherein the patient has suffered a spinal injury within 12 hours of commencing treatment.
39. The method of claim 35 , wherein the patient has suffered a spinal injury within 6 hours of commencing treatment.
40. The method of claim 35 , wherein the patient has suffered a spinal injury within 3 hours of commencing treatment.